One clinical trial is presently underway as part of this project. The clinical trial is a single-center randomized, double-blinded, placebo-controlled study involving 170 diabetic Pima Indian adults with normal urinary albumin excretion or microalbuminuria. It was designed to determine whether blockade of the angiotensin II receptor with losartan will prevent or further attenuate the development and progression of early diabetic nephropathy in subjects with type 2 diabetes mellitus who are receiving standard diabetes care that now includes treatment with the angiotensin converting enzyme inhibitor lisinopril. Subjects in each albumin excretion group were randomized to treatment with either losartan, or placebo. Measurements of glomerular filtration rate, renal plasma flow and fractional clearances of albumin and IgG were made using standard urinary clearance methods as outlined in Project Number Z01 DK069063-12. These tests were performed initially, at one month, and at 12-month intervals from baseline thereafter. The primary outcome measure is a decline in GFR to less than 60 ml/min or to half the baseline value in subjects that enter the study with a GFR of <120 ml/min. A kidney biopsy was performed after 5.5 years in 122 of these subjects. Morphometric analysis of kidney biopsies, as reported in Project Number Z01 DK069100-01, will be used to determine differences in the prevalence of global sclerosis, the number of visceral epithelial cells per glomerulus, and the breadth of epithelial foot processes between treatment groups. Differences in a severity index computed from the joint distribution of these morphometric variables will be used to assess the renoprotective efficacy of losartan at the tissue level. Following the kidney biopsy and after the 72-month renal clearance study, treatment with all ACEi and ARBs will be stopped for six weeks. At the end of the six-week washout period a second clearance study will be performed. Randomized study treatment will end at that time, but quarterly follow-up visits and annual renal clearance studies will continue to the onset of kidney failure. This project, in part, represents extensions of work previously reported as Project Number Z01 DK69037. We completed the randomized treatment portion of the losartan clinical trial four years ago and we completed the laboratory assays of glomerular filtration rate and renal plasma flow last year. We are performing morphometric analyses on the kidney biopsies as described in Project Number Z01 DK069100-01 and about two thirds of the biopsies are now complete. In addition, portions of the kidney tissue from each patient underwent laser microdissection to separate the tubular and glomerular components, and gene expression and methylation studies are being conducted on these tissues. Results of these expression studies will be correlated with the appearance of various urinary biomarkers. This project is expected to yield new insights into the management of kidney disease in type 2 diabetes.